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1 2 ) United S t a t e s PatentP a t h i e t a 1 .

US008269003B2

US 8 , 2 6 9 , 0 0 3 B2S e p . 1 8 , 2 0 1 2

1 0 ) Patent N 0 . :

4 5 ) Date o f P a t e n t :

5 4 ) STABLE CRYSTAL FORMOFIMATINIB

MESYLATE AND PROCESS FOR THE

PREPARATION THEREOF

7 5 ) I n v e n t o r s : S r i n i v a s L a X m i n a r a y a n P a t h i ,B a n g a l o r e I N ) ; R e v i k u m a r P u p p a l a ,

B a n g a l o r e I N ) ; R a j e n d r a N a r a y a n r a oK a n k a n , Mumbai I N ) ; D h a r m a r a jRamachandra R a o , Mumbai I N )

7 3 ) A s s i g n e e : CIPLA L i m i t e d , Mumbai I N )

o t i c e : u ect to an 1 s c a1mer, t e term 0 t sN S b j yd' l h f h i

p a t e n t i s e x t e n d e d o r a d j u s t e d u n d e r 3 5

U . S . C . 1 5 4 b ) b y 9 3 7 d a y s .

2 1 ) A p p l . N o . : 1 1 / 5 7 4 , 6 4 2

2 2 ) PCT i l e d : S e p . 2 , 2 0 0 5

8 6 ) PCT N o . : PCT/GB2005/003392

§ 3 7 1 0 X 1 ) ,2 ) , 4 ) D a t e : May 3 , 2 0 0 7

8 7 ) PCT P u b . N o . : WO2006/024863

PCT P u b . D a t e : Mar. , 2006

6 5 ) P r i o r P u b l i c a t i o n D a t a

US 2007/0265288 A1 N o v . 1 5 , 2007

3 0 ) F o r e i g n A p p l i c a t i on P r i o r i t y D a t a

Sep. 2 , 2004 (IN) . . . . . . . . . . . . . . . . . . . . . . . . . . . 951/MUM/2004

5 1 ) I n t . C l .

C07D 4 1 1 / 0 0 2 0 0 6 . 0 1 )

5 2 ) US. l . . . . . . . . . . . . . . . . . . . . . . . 544/333; 544/360; 546/268.1

(58) Field of Classi?cation S e a r c h . . . . . . . . . . . . . . . . . . 544/333,

5 4 4 / 3 6 0 ; 5 4 6 / 2 6 8 . 1

S e e a p p l i c a t i on ? l e f o r c o m p l e t e s e a r c h h i s t o r y .

5 6 ) R e f e r e n c e s C i t e d

U . S . PATENT DOCUMENTS

5 , 5 2 1 , 1 8 4 A 5 / 1 9 9 6 Zimmermann

FOREIGN PATENT DOCUMENTS

EP 0 564 409 Al 1 0 / 1 9 9 3

GB 2 398 565 A 8/2004

W0 WO 9/03854 A1 1 / 1 9 9 9W0 WO 004/106326 A1 1 2 / 2 0 0 4

W0 WO 005/077933 A1 8 / 2 0 0 5

W0 WO 005/095379 A2 1 0 / 2 0 0 5

OTHERPUBLICATIONS

C h o i , e t a 1 . I n t . J . M i n e r . P r o c e s s , 7 4 S , 2 0 0 4 , S 1 6 5 - S 1 7 2 . *

F o r e i g n c o m m u n i c at i o n f r o m a r e l a t e d c o u n t e r p a r t a p p l i c a t i o n i

I n t e r n a t i o n a l S e a r c h R e p o r t , P C T / G B 2 0 0 5 / 0 0 3 3 9 2 , D e c . 1 5 , 2 0 0 5 , 4

p a g e s .

F o r e i g n c o m m u n i c at i o n f r o m a r e l a t e d c o u n t e r p a r t a p p l i c a t i o n i

I n t e r n a t i o n a l P r e l i m i n a r y R e p o r t o n P a t e n t a b i l i t y , PCT/GB2005/

0 0 3 3 9 2 , M a r . 6 , 2 0 0 7 , 8 p a g e s .

* c i t e d b y examiner

Primary Exam iner* ouglas M i l l i s

7 4 ) A t t o r n e y , A g e n t , o r F i r m * o n l e y R o s e , P . C . ; RodneyB . C a r r o l l

5 7 ) ABSTRACT

The i n v e n t i o n r e l a t e s to i m a t i n i b f o r u s e i n tumor t h e r a p y .

T h i s i n v e n t i o n d e s c r i b e s a s t a b l e , non y g r o s c o p i c a l p h a c r y s

t a l l i n e f o r m o f methane s u l f o n i c a c i d a d d i t i o n s a l t o f 4 - 4

m e t h y l p i p e r a Z i n - - y l m e t h y l ) - N - [ 4 - m e t h y l - 3 - 4 - p y r i d i n -3

y l ) - p y r i m i d i n - 2 - y l a m i n o ) p h e n y l ] - b e n Z a m i d e i m a t i n i bm e s y l a t e ) h a v i n g t h e g e n e r a l s t r u c t u r a l f o r m u l a

/N OH

A r o c e s s f o r t h e p r e p a r a t i o n o f t h e c r y s t a l l i n e f o r m i s a l s o

d e s c r i b e d .

8 C l a i m s , 2 Drawing S h e e t s

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US. Patent S e p . 1 8 , 2 0 1 2 S h e e t 1 o f 2 US 8 , 2 6 9 , 0 0 3 B2

0 8 8Q ?Q 8

2 ?Q 5 8

0 0 0 0 ?

I O O O Fo o o wo o o mo o o wm

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US 8 , 2 6 9 , 0 0 3 B2

1

STABLE CRYSTAL FORMOF IMATINIB

MESYLATE AND PROCESS FOR THE

PREPARATION THEREOF

CROSS-REFERENCETO RELATED 5

APPLICATIONS

T h i s a p p l i c a t i o n i s a ? l i n g u n d e r 3 5 U . S . C . 3 7 1 o f n t e r n a

t i o n a l A p p l i c a t i o n N o . PCT/GB2005/003392 ? l e d S e p . 2 ,

2 0 0 5 , e n t i t l e d “ S t a b l e C r y s t a l Form f m a t i n i b M e s y l a t e a n d

P r o c e s s f o r t h e P r e p a r a t i o n T h e r e o f , ” c l a i m i n g p r i o r i t y o f

I n d i a n P a t e n t A p p l i c a t i o n N o . 95l/MUM/2004 ? l e d S e p . 2 ,

2 0 0 4 , W h i c h a p p l i c a t i o n s a r e i n c o r p o r a t e d b y r e f e r e n c e

h e r e i n i n t h e i r e n t i r e t y .

STATEMENT REGARDING FEDERALLY

SPONSORED RESEARCH OR DEVELOPMENT

NtA l ~ bl.pp1ca e 20

THE NAMES OFTHE PARTIES TOA OINT

RESEARCH AGREEMENT

N o t A p p l i c a b l e .25

INCORPORATIONBY REFERENCE OF

MATERIAL SUBMITTED ONA COMPACT ISC

N o t A p p l i c a b l e .30

BACKGROUND OFTHE INVENTION

1 . F i e l d o f t h e I n v e n t i o n

The r e s e n t i n v e n t i o n r e l a t e s t o a s t a b l e c r y s t a l form o f t h e

m e t h a n e s u l f o n i c a c i d a d d i t i o n s a l t o f 4 - 4 - m e t h y l p i p e r a Z i n

l - y l m e t h y l ) - N - 4 - m e t h y l - 3 - 4 - p y r i d i n - 3 - y l ) - p y r i m i d i n - 2 - y la m i n o ) p h e n y l ] - b e n Z a m i d e o f F o r m u l a , a n d t o a p r o c e s s f o r

t he p r e p a r a t i o n t h e r e o f . T h e c r y s t a l f o r m a c c o r d i n g t o t h ei n v e n t i o n may b e u s e d i n t h e p r e p a r a t i o n o f p h a r m a c e u t i c a l

f o r m u l a t i o n s f o r u s e i n tumor t h e r a p y .

2 . D e s c r i p t i o n o f R e l a t e d A r t

I m a t i n i b i s t h e i n t e r n a t i o n a l n o n - p r o p r i e t a r y name o f - 4

m e t h y l p i p e r a Z i n - l - y l m e t h y l ) - N - [ 4 - m e t h y l - 3 - 4 - p y r i d i n - 3y l ) - p y r i m i d i n - 2 - y l a m i n o ) p h e n y l ] - b e n Z a m i d e . I m a t i n i b i sc u r r e n t l y u s e d f o r t h e t r e a t m e n t o f a ti e nt s W i t h c e r t a i n t y p e s

o f l e u k a e m i a m o s t c o m m o n l y c h r o n i c m y e l o i d l e u k a e m i a )

and a r a r e type of cancer kn oWn a s g a s t r o - i n t e s t i n a l s t r o m a l

t u m o u r G I S T ) . The s t r u c t u r a l f o r m u l a o f i m a t i n i b i s g i v e n

b e l o W .

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EP564409 and U S . P a t . No. 5 , 5 2 1 , 1 8 4 ? r s t r e p o r t e d a 6 5

p r o c e s s f o r p r e p a r a t i o n o f 4 - 4 - m e t h y l p i p e r a Z i n - l - y lm e t h y l ) - N - [ 4 - m e t h y l - 3 - 4 - p y r i d i n - 3 - y l ) - p y r i m i d i n - 2 - y l

2

a m i n o ) p h e n y l ] b e n Z a m i d e o f F o r m u l a I a n d t h e u s e th e r e o f ,

e s p e c i a l l y a s an a n t i - t u m o r a g e n t . HoWever, i t d o e s n o t

s p e c i f y a n y c r y s t a l m o d i ? c a t i o n s .

P a t e n t A p p l i c a t i o n WO 9 / 0 3 8 5 4 d i s c l o s e d t W o p o l y m o r

p h i c f o r m s o f Methane s u l f o n ic a c i d a d d i t i o n s a l t o f i m a t i n i b

I m a t i n i b M e s y l a t e ) v i Z : a n o r ) A l p h a c r y s t a l f o r m a n d a [ 3 )

B e t a c r y s t a l f o r m a n d t h e p r o c e s s e s f o r t h e i r p r e p a r a t i o n . The

p r o c e s s f o r t h e p r e p a r a t i o n o f h e a l p h a c r y s t a l l i n e f o r m c o m

p r i s e s s u s p e n d i n g i m a t i n i b b a s e i n e t h a n o l , a d d i n g m e t h a n e

s u l f o n i c a c i d d r o p W i s e t o t h e s a i d s o l u t i o n , h e a t i n g t h e s o l u

t i o n t o r e ? u x a n d ? l t e r i n g ; e v a p o r a t i n g t h e ? l t r a t e t o 50 ,

? l t e r i n g o f f the r e s i d u e ; e v a p o r a t i n g t h e m o t h e r l i q u o r t od r y n e s s ; s u s p e n d i n g t h e r e s i d u e a n d ? l t e r e d ma t e r i a l i n e t h a

n o l ; d i s s o l v i n g u n d e r r e ? u x c o n d i t i o n s b y s i m u l t a n e o u s l y

a d d i n g a t e r ; c o o l i n g o v e r n i g h t , ? l t e r i n g a n d d r y i n g o o b t a i na l p h a c r y s t a l l i n e f o r m . T h e o b t a i n e d l p h a - c r y s t a l l i n e f o r m s

n o t s t a b l e , i s h i g h l y h yg r o s c o p i c , i s a m o r p h o u s i n n a t u r e a n d

n o t u s e f u l f o r t h e p r e p a r a t i o n o f h a r m a c e u t i c a l p r e p a r a t i o n s .

T h e p r e v i o u s l y knoWn m e t h o d f o r p r o d u c i n g the a l p h a

c r y s t a l f o r m o f methane s u l f o n i c a c i d a d d i t i o n s a l t o f t h e

compound o f F o r m u l a i n v o l v e s t h e p r e c i p i t a t i o n o f t h e s a l t

from t s s o l u t i o n in n o n - a l c o h o l i c s o l v e n t s . I t h a s a l s o been

a c k n o w l e d g e d in t h e p r i o r r t t h a t t h e o t - c r y s t a l f o r m o b t a i n e d

b y such a p r o c e s s Was i n c o n s i s t e n t and hence had an unde

s i r a b l e p r o p e r t y s u c h a s h y g r o s c o p i c n a t u r e and n f a v o u r a b l e

? o W c h a r a c t e r i s t i c s . I t Was t h u s an u n s t a b l e c r y s t a l form and

u n s u i t e d f o r p h a r m a c e u t i c a l p r e p a r a t i o n s .The knoWn p r o c e s s f o r p r e p a r i n g t h e b e t a - c r y s t a l f o r m

involves use of an a l c o h o l i c solvent such a s methan o l or

e t h a n o l , o r a mixture of acetone and Water o r dimethyl f o r

mamide a n d c r y s t a l l i Z a t i o n i s i n d u c e d b y s e e d i n g .

BRIEF SUMMARY OFTHE INVENTION

The r e s e n t i n v e n t i o n r e l a t e s t o a c r y s t a l l i n e form o f meth

a n e s u l f o n i c a c i d a d d i t i o n s a l t o f 4 - 4 - m e t h y l p i p e r a Z i n - l - y l

m e t h y l ) - N - [ 4 - m e t h y l - 3 - 4 - p y r i d i n - 3 - y l ) - p y r i m i d i n - 2 - y l

a m i n o ) p h e n y l ] - b e n Z a m i d e i m a t i n i b m e s y l a t e ) . M o r e s p ec i ? c a l l y , t h e i n v e n t i o n r e l a t e s t o t h e a l p h a c r y s t a l l i n e f o r m o f

i m a t i n i b m e s y l a t e .

I t i s i m p o r t a n t t o u n d e r s t a n d t h a t the c r y s t a l l i n e p o l y m o r

p h i c f o r m o f i m a t i n i b m e s y l a t e a c c o r d i n g o t h e i n v e n t i o n n o t

t h e same m a t e r i a l a s i s d e s c r i b e d i n W0 9 / 3 8 5 4 . The a l p h a

i m a t i n i b m e s y l a t e d e s c r i b e d i n WO 9/03854 i s n o t a s t a b l e

c o m p o u n d , W h e r e a s t h e a l p h a i m a t i n i b m e s y l a t e a c c o r d i n g ot h e i n v e n t i o n i s s t a b l e .

The t e r m “ s t a b l e ” a s u s e d i n t h i s s p e c i ? c a t i o n p r e f e r a b l y

means t h a t t h e i m a t i n i b m e s y l a t e r e t a i n s polymorphic o r

c h e m i c a l s t a b i l i t y f o r a t l e a s t t h r e e m o n t h s , more p r e f e r a b l y

f o r a t l e a s t s i x m o n t h s , and most r e f e r a b l y f o r t l e a s t t W e l v e

m o n t h s . More p r e f e r a b l y , t h e term “ s t a b l e ” a s used i n t h i s

s p e c i ? c a ti o n p r e f e r a b l y means t h a t the i m a t i n i b m e s y l a t e

r e t a i n s p o l y m o r p h i c a n d c h e m i c a l s t a b i l i t y f o r a t l e a s t t h r e e

m o n t h s , more p r e f e r a b l y f o r a t l e a s t s i x m o n t h s , and most

p r e f e r a b l y f o r a t l e a s t t W e l v e m o n t h s .

The n v e n t i o n a l s o r e l a t e s t o a p r o c e s s f o r t h e p r e p a r a t i o n of

s a i d c r y s t a l l i n e f o r m o f i m a t i n i b m e s y l a t e . The p r o c e s s

a c c o r d i n g t o t h e i n v e n t i o n makes i t p o s s i b l e t o p r o d u c e a

c r y s t a l l i n e form o f methane s u l f o n i c a c i d a d d i t i o n s a l t o f

i m a t i n i b i n a form Which s s t a b l e and n o n - h y g r o s c o p i c . We

h a v e f o u n d t h a t t h e s t a b l e , n o n - h y g r o s c o p i c c r y s t a l l i n e f o r m

o f methane s u l f o n i c a c i d a d d i t i o n s a l t o f i m a t i n i b h a s n e e d l e

s h a p e d r y s t a l s . T h e t a b l e , n o n - h y g r o s c o p i c r y s t a l l i n e f o r mof methane s u l f o n i c a c i d a d d i t i o n s a l t of i m a t i n i b can be

p r o d u c e d i n a n e s s e n t i a l l y p u r e c r y s t a l f o r m .

T h u s , t h e i n v e n t i o n r e l a t e s t o a p r o c e s s f o r p r e p a r i n g t h e

a l p h a - c r y s t a l l i n e form o f methane s u l f o n i c a c i d a d d i t i o n s a l t

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o f i m a t i n i b and a l s o t o a s t a b l e , n o n - h y g r o s c o p i c form o f t h e

s a l t i t s e l f . T h i s s a l t i s v e r y s u i t a b l e f o r t h e p r e p a r a t i o n o f

p h a r m a c e u t i c a l f o r m u l a t i o n s .

BRIEF DESCRIPTION OFTHE SEVERAL

VIEWS OF THE DRAWING(S)

F I G . 1 s h o W s the X - r a y d i f f r a c t i o n d i a g r a m o f t h e a l p h a

c r y s t a l f o r m o f t h e methane s u l f o n i c a c i d a d d i t i o n s a l t o f

compound o f F o r m u l a I , a c c o r d i n g t o t h e p r e s e n t i n v e n t i o n .T h e X - r a y d i f f r a c t i o n d i a g r a m o f t h e a l p h a - c r y s t a l f o r m i s

c h a r a c t e r i z e d b y p e a k s a t 2 - t h e t a 4 . 8 7 ° , l 0 . 4 0 ° l 8 . 5 6 ° a n d

2 4 . 8 2 ° and b s e n c e o f p e a k s a t 5 8 7 ° , 972° and 200° t h a t a r e

c h a r a c t e r i s t i c o f t h e [ 3 - f o r m .F I G . 2 shoWs t h e DSC o f t h e a l p h a - c r y s t a l form o f t h e

methane s u l f o n i c a c i d a d d i t i o n s a l t o f c om p ound o f F o r m u l a

I , a c c o r d i n g t o t h e p r e s e n t i n v e n t i o n . T h e a l p h a - c r y s t a l f o r m

o f t h e methane s u l f o n i c a c i d a d d i t i o n s a l t o f a c o m po u nd o f

F o r m u l a I a c c o r d i n g t o t h e i n v e n t i o n h a s a m e l t i n g p o i n t ,

e s p e c i a l l y betWeen 221-228° C . a s i n d i c a t e d i n F I G . 2 .

DETAILED DESCRIPTION OFTHE INVENTION

The r e s e n t i n v e n t i o n r e l a t e s t o a p r o c e s s f o r p r e p a r a t i o n o f

a s t a b l e , n o n - h y g r o s c o p i c a l p h a - c r y s t a l l i n e f o r m o f m e t h a n e

s u l f o n i c a c i d a d d i t i o n s a l t o f 4 - 4 - m e t h y l p i p e r a Z i n e - l y lm e t h y l ) - N - [ 4 - m e t h y l - 3 - 4 - p y r i d i n - 3 - y l ) - p y r i m i d i n - 2 - y la m i n o ) p h e n y l ] b e n Z a m id e i m a t i n i b m e s y l a t e ) o f F o r m u l a .I t h a s a l s o been t e s t e d and found t h a t t h i s form s v e r y W e l l

s u i t e d f o r u s e i n p h a r m a c e u t i c a l f o r m u l a t i o n s .

I m a t i n i b b a s e may b e p r e p a r e d a c co r d i n g t o p r o c e s s e s

d e s c r i b e d i n p r i o r a r t a s f o r example i n EP 5 6 4 4 0 9 .

A c c o r d i n g t o one a s p e c t o f t h e p r e s e n t i n v e n t i on t h e r e i s

p r o v i d e d a p r o c e s s f o r t h e p r e p a r a t i o n o f a p u r e , n o n - h y g r o

s c o p i c a n d s t a b l e a l p h a c r y s t a l f o r m o f h e m e t h a n e s u l f o n i ca c i d a d d i t i o n s a l t o f 4 - 4 - m e t h y l p i p e r a Z i n e - l - y l m e t h y l ) - N

[ 4 - m e t h y l - 3 - 4 - p y r i d i n - 3 y l ) - p y r i m i d i n - 2 y l a m i n o ) p h e n y l ]benZamide of F orm ula I . H

HN N N

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The r o c e s s a c c o r d i n g t o t h e i n v e n t i o n i s c h a r a c t e r i s e d by

t h e s t e p s o f :

a ) s u s p e n d i n g o r d i s s o l v i n g t h e compound f t h e F o r m u l a

I i n a s o l v e n t ;

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b ) a d d i n g methane s u l f o n i c a c i d a t a c o nt r o l l e d r a t e and t

p r e d e t e r m i n e d t e m p e r a t u r e t o a b o v e s u s p e n s i o n o r s o l u

t i o n ;c ) h e a t i n g t h e a b o v e m i x tu r e f o r a s u ? i c i e n t amount o f

t i m e t o i n d u c e t h e f o r m a t i o n o f a l p h a c r y s t a l f o r m ;

d ) c o o l i n g t h e m i x t u r e t o a m b i e n t t e m p e r a t u r e a n d i s o l a t

i n g t h e a l p h a c r y s t a l f o r m ; a n d , o p t i o n a l l y ,e ) m i c r o n i Z i n g t h e c r y s t a l s in a n a i r j e t m i l l t o o b t a i n t h e

r e q u i r e d p a r t i c l e s i Z e .

P r e f e r a b l y th e c o o l i n g t o a m b i e n t t e m p e r a t u r e i n s t e p d )

i n v o l v e s c o o l i n g t o 2 5 - 3 0 ° C .

I n s t e p b ) , t h e m i x t u r e i s p r e f e r a b l y h e a t e d to a t l e a s t a b o u t

7 0 ° C . , more r e f e r a b l y a t l e a s t a b o u t 7 5 ° C . , most r e f e r a b l y

a t l e a s t a b o u t 8 0 ° C .

The i s o l a t i o n i n s t e p d ) may b e a c h i e v e d b y ? l t r a t i o n ,p r e f e r a b l y f o l l o W e d b e d r y i n g u n d e r r e d u c e d r e s s u r e . Imme

d i a t e l y a f t e r ? l t r a t i o n , t h e ? l t r a t e i s p r e f e r a b l y d i s s ol v e d o r

suspended i n a s o l v e n t , such s a C2 t o C4 a l c o h o l o r a k e t o n e .

The s o l v e n t m a y be t h e same a s t h e s o l v e n t used i n s t e p a ) .

P r e f e r a b l y t h e s o l v e n t i s i s o p r o p y l a l c o h o l .I t W i l l b e n o t e d t h a t t h e a l p h a c r y s t a l f o r m o f i m a t i n i b

m e s y l a t e o b t a i n e d b y the p r o c e s s o f t h e p r e s e n t i n v e n t i o n

i n v o l v e s r e ? u x i n g , f o l l o W e d b y c o o l i n g a n d i s o l a t i o n o f t h e

c r y s t a l s . The c o n t r a s t s W i t h t h e p r o c e s s in WO99/03854,

W h e r e t h e p r o c e s s i n v o l v e s r e ? u x i n g , c o o l i n g , ? l t r a t i o n ,e v a p o r a t i o n o d r y n e s s , s u s p e n s i o n n e t h a n o l , r e ? u x i n g , a d d

i n g W a t e r , c o o l i n g a n d ? l t e r i n g t h e a l p h a f o r m . T h i s muchmore c o m p l e x p r o c e s s a p p a r e n t l y p r o d u c e s t h e a l p h a f o r m i n

a s t a t e Which i s l e s s s t a b l e and m o r e h y g r o s c o p i c t h a n t h e

p r o d u c t p r o d u c e d i n a c c o r d a n c e W i t h t h e p r o c e s s o f t h e

p r e s e n t i n v e n t i o n . I t W i l l be a r t i c u l a r l y n o t e d t h a t an advan

t a g e o u s f e a t u r e o f h e p r e s e n t i n v e n t i o n s t h a t W a t e r , p e r s e , i s

n o t added t any s t a g e of h e p r o c e s s .

The r e s e n t i n v e n t io n p r o v i d e s a p r o c e s s f o r p r o d u c i n g an

e s s e n t i a l l y p u r e a l p h a f o r m o f i m a t i n i b m e s y l a t e W h i c h i s

r e l a t i v e l y s t a b l e a s i n d i c a t e d i n the f o r c e d d e g r a d a t i o n s t u d

iesiTable 2 ) Which c a n b e s u i t e d t o p r e p a r e p h a r m a c e u ti c a l

f o r m u l a t i o n s .The a l p h a - c r y s t a l f o r m o f i m a t i n i b m e s y l a t e i s c h a r a c t e r

i Z e d b y n e e d l e s h a p e d c r y s t a l s . T h u s , a c c o r d i n g t o a n o t h e r

a s p e c t o f t h e i n v e n t i o n t h e r e i s p r o v i d e d a n c r y s t a l f o r m

p r e f e r a b l y a l p h a c r y s t a l f o r m ) o f i m a t i n i b m e s y l a t e W h i c h

c o m p r i s e s n e e d l e s h a p e d r y s t a l s . P r e f e r a b l y , t h e c r y s t a l f o r m

p r e f e r a b l y a l p h a c r y s t a l f o r m ) o f m a t i n i b m e s y l a t e c o n s i s t se s s e n t i a l l y o f n e e d l e s h a p e d c r y s t a l s .

The t e r m “ e s s e n t i a l l y p u r e ” i s u n d e r s t o o d i n t h e c o n t e x t o f

t h e p r e s e n t i n v e n t i o n t o m e an s p e c i a l l y t h a t a t l e a s t 9 0 Wt ,

p r e f e r a b l y a t l e a s t 9 5 Wt , and most p r e f e r a b l y a t l e a s t 9 9

Wt f h e c r y s t a l s of an a c i d a d d i t i o n s a l t o f Formula I a r e

p r e s e n t i n the c r y s t a l f o r m a c c o r d i n g t o the i n v e n t i o n , e s p e

c i a l l y t h e o t - c r y s t a l f o r m .

I n t h e p r e f e r r e d e m b o d i m e n t , the e s s e n t i a l l y p u r e m e t h a n e

s u l f o n i c a c i d a d d i t i o n s a l t o f a c o m po u nd o f Formula i n t h e

a l p h a - c r y s t a l f o r m s h o W s t h e X - r a y d i f f r a c t i o n d i a g r a m i n d ic a t e d in F I G . 1 . The a l p h a - c r y s t a l form o f t h e methane s u l

f o n i c a c i d a d d i t i o n s a l t o f a c o m po u nd f Formula Which a s

a m e l t i n g r a n g e , e s p e c i a l l y betWeen 2 1 - 2 2 8 ° C . a s i n d i c a t e d

i n F I G . 2 . According t o a f u r t h e r a s p e c t o f t h e i n v e n t i o n t h e r e

i s p r o v i d e d a c r y s t a l f o r m p r e f e r a b l y a n a l p h a c r y s t a l f o r m )

o r i m a t in i b m e s y l a t e h a v i n g a m e l t i n g p o i n t i n t h e r a n g e

221-228° C . , o r 221-225° C .

M e l t i n g p o i n t s Were d e t e r m i n e d by means o f a DSC h e r

m o g r a m . D S C [ “ d i f f e r e n t i a l s c a n n i n g c a l o r i m e t r y ” ] i s t h e

t e c h n i q u e o f d y n a m i c d i f f e r e n t i a l c a l o r i m e t r y . U s i n g t h i s

t e c h n i q u e , t h e m e l t i n g t e m p e r a t u r e b o t h o f h e a l p h a - c r y s t a lf o r m a n d o f t h e b e t a - c r y s t a l f o r m c a n b e m e a s u r e d b y h e a t i n g

t h e samples u n t i l a t h e r m a l i . e . , an endothermic o r e x o t h e r

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5

m i c , r e a c t i o n i s d e t e c t e d by means o f DSC e t e c t o r s . The

m e l t i n g p o i n t i n d i c a t e d i n t h i s t e x t Was d e t e r m i n e d u s i n g

SchimadZu DSC 50 a p p a r a t u s , a b o u t 2 . 0 to 3 . 0 mg f e a c h

sample b e i n g measured i n an aluminium c r u c i b l e W i t h a p e r

f o r a t e d l i d u n d e r N i t r o g e n a t m o s p h e r e a t a h e a t i n g r a t e o f 5 °

C . / m i n . [ s t a r t i n g a t a m b i e n t t e m p e r a t u r e up o 3 0 0 ° C . ] .

T h e X - r a y d i f f r a c t i o n d i a g r a m W a s r e c o r d e d u s i n g R i g a k u

Min?ex M a k e ) W1Ihi

s t a r t a n g l e 3 . 0 0 d e g .

s t o p a n g l e 5 0 . 0 0 d e g .S c a n s p e e d 2 . 0 0 d e g / m i n .

S c a t t e r i n g 4 . 2 d e g .C o u n t i n g U n i t c p s

XG ower 3 0 KV, 1 5 MA

D i v e r g e n c e V a r i a b l e

I n i t i a l s c a l e 1000 c p s

Measurement method Continuous

D e t e c t o r t y p e S c i n t i l l a t i o n c o u n t e r

So urce Cu K X X 1.54°A

A c c o r d i n g t o a n o t h e r a s p e c t o f t h e p r e s e n t i n v e n t i o n , t h e r e

i s p r o v i d e d a l p h a c r y s t a l f o r m o f i m a t i n i b m e s y l a t e , W h i c hcan be c h a r a c t e r i s e d a s h a v i n g an X-ray d i f f r a c t i o n p a t t e r n

W i t h c h a r a c t e r i s t i c p e a k s 2 0 ) a s i n T a b l e 1 .

TABLE

Peak 20 FWHM d I n t e n s i t y

N o . d e g ) d e g ) A ) C o u n t s ) U 1 0

1 4.870 0 . 1 6 5 18.1296 573 14

2 1 0 . 4 0 0 0 . 2 1 2 8.4987 2099 5 1

3 1 1 . 1 5 0 0 . 3 1 8 7.9286 462 1 2

4 1 1 . 8 4 0 0 . 2 7 1 7.4681 640 1 6

5 1 2 . 1 3 0 0 . 2 0 0 7.2902 517 1 3

6 1 4 . 8 5 0 0 . 2 8 2 5.9604 1939 47

7 1 6 . 4 4 0 0 . 2 8 2 5.3874 1143 28

8 1 7 . 6 2 0 0 . 4 3 5 5.0291 2390 58

9 1 8 . 0 4 0 0 . 2 5 9 4.9130 2489 60

1 0 1 8 . 5 6 0 0 . 2 8 2 4.7765 4191 100

1 1 1 9 . 0 1 0 0 . 2 5 9 4.6644 3205 77

1 2 1 9 . 7 8 0 0 . 1 4 1 4.4846 690 1 7

1 3 21.200 0.294 4.1873 3197 77

14 21.480 0 . 1 1 8 4.1333 2941 7 1

1 5 21.620 0 . 1 7 6 4.1069 2832 68

1 6 22.400 0 . 1 1 8 3.9656 1064 26

1 7 22.570 0 . 1 8 8 3.9361 1320 32

1 8 23.090 0 . 2 5 9 3.8486 1505 36

1 9 23.690 0 . 2 7 1 3.7525 1657 40

20 24.820 0 . 3 1 8 3.5842 3030 73

2 1 26.230 0 . 2 0 0 3.3946 753 1 8

22 27.190 0 . 4 5 9 3.2769 1177 29

23 27.840 0 . 1 1 8 3.2018 1323 32

24 27.960 0 . 1 2 9 3.1884 1497 36

25 28.460 0 . 3 4 1 3.1335 2741 66

26 31.870 0 . 2 0 0 2.8056 852 2 1

27 38.000 0.224 2.3659 771 1 9

28 38.950 0 . 2 0 0 2.3103 772 1 9

29 39.200 0 . 1 0 6 2.2962 820 20

30 39.390 0 . 1 6 5 2.2855 918 22

3 1 39.550 0 . 1 2 9 2.2767 892 22

32 42.950 0 . 1 1 8 2.1040 830 20

33 43.050 0 . 2 0 0 2.0993 889 22

34 43.290 0 . 1 0 6 2.0882 856 2 1

35 45.540 0 . 1 0 6 1.9902 801 20

36 45.960 0 . 1 0 6 1.9729 854 2 1

The p r o c e s s o f t h e p r e s e n t i n v e n t i o n c a n b e c o n v e n i e n t l y

c a r r i e d o u t i n a l c o h o l i c o r k e t o n i c s o l v e n t s . The a i d a l c o h o l i c

s o l v e n t s may b e s e l e c t e d f r o m C 2 t o C4 l c o h o l s , p r e f e r a b l y

i s o p r o p a n o l o r n - b u t a n o l . The k e t o n i c s o l v e n t i s p r e f e r a b l y

m e t h y l - i s o b u t y l k e t o n e .T h e r e f e r r e d m e t h o d o f r e p a r a t i o n c o m p r i s e s d i s s o l v i n g

o r s u s p e n d i n g t h e c om p ound o f F o r m u l a I in t h e s e l e c t e d

20

25

30

35

40

45

50

55

60

6 5

6

s o l v e n t , f o r e x a m p l e i s o p r o p a n o l , a d d i n g m e t h a n e s u l f o n i ca c i d i n a c o n t r o l l e d manner and o p t i o n a l l y h e a t i n g t h e con

t e n t s t o a t e m p e r a t u r e above a m b i e n t t o t h e b o i l i n g p o i n t o f

t h e s o l v e n t , m a i n t a i n i n g a t t h e d e s i r e d t e m p e r a t u r e f o r a ?xed

p e r i o d o f t i m e t o a l l o W t h e c r y s t a l l i z a t i o n o f t h e methane

s u l f o n i c a c i d s a l t o f Formula t o b e c r y s t a l l i Z e d i n t h e d e s i r e d

f o r m , f o l l o W e d b y c o o l i n g t o a m b i e n t t e m p e r a t u r e a n d ? l t e ri n g t h e d e s i r e d c r y s t a l s . The r y s t a l s may e d r i e d a t e l e v a t e d

t e m p e r a t u r e s u n d e r v ac u u m and m a y be f u r t h e r s u b j e c t e d t o

m i l l i n g o r m i c r o n i Z a t i o n .

A a r t i c u l a r l y s t r i k i n g f e a t u r e o f t h e p r o c e s s a c c o r d i n g t ot h e i n v e n t i o n s t h a t t h e p r o d u c t c a n b e o b t a i n e d i n t h e d e s i r e d

f o r m W i t h o u t r e s o r t i n g t o s e e d i n g , W h i c h i s r e q u i r e d f o r p r o

d u c i n g t h e b e t a - f o r m a s d i s c l o s e d i n WO9903854. The p r o

c e s s o f t h e p r e s e n t i n v e n t i o n i s v e r y s u i t a b l e f o r i n d u s t r i a l

a p p l i c a t i o n , p a r t i c u l a r l y a s a p h a r m a c e u t i c a l . The i m a t i n i b

m e s y l a t e a c c o r d i n g t o t h e i n v e n t i o n i s s u i t a b l e f o r u s e i n

t h e r a p y . I t i s u s e f u l i n m e t h o d s o f r e a t i n g c a n c e r , p a r t i c u l a r l y

l e u k a e m i a m o s t c o m m o n l y h r o n i c m y e l o i d l e u k a e m i a ) a n dGIST. t i s a l s o u s e f u l i n t h e manufacture of medicament f o r

t r e a t i n g s u c h d i s e a s e s .A t r e s s s t u d y Was e r f o r m e d on h e a l p h a form f m a t i n i b

M e s y l a t e b y u s i n g v a r i o u s c o n d i t i o n s , s u c h as e x p o s u r e t o

h i g h e r t e m p e r a t u r e s , f o r e x a m p l e 6 0 0 C . f o r 4 8 h o u r s , 1 0 5 0 C .

f o r 1 2 h o u r s , and UV 5 ° C . a t 75 RH o r a p e r i o d o f 1 2

h o u r s . T h e s t u d y s h o W e d t h a t t h e a l p h a i m a t i n i b m e s y l a t e

p r o d u c e d i n a c c o r d a n c e W i t h t h e p r e s e n t i n v e n t i o n i s q u i t e

s t a b l e a s i n d i c a t e d T a b l e 2 Wherein t h e r e i s no i n c r e a s e i n t h e

l e v e l o f i m p u r i t i e s b e f o r e a n d a f t e r s t a b i l i t y s t u d y a n d t h e

p r o d u c t i s p o l y m o r p h i c a l l y s t a b l e When D S C a n d XRPD

e v a l u a t i o n Was p e r f o r m e d on b o t h t h e s a m p l e s . The p r o d u c t

o n s t o r a g e Was found to b e s t a b l e c h e m i c a l l y and polymor

p h i c a l l y a t a m b i e n t t e m p e r a t u r e .

U n l i k e many s u b s t a n c e s , W h i c h l o s e t h e i r p o l y m o r p h i c

i d e n t i t y When u b j e c t e d t o s t r e s s c o n d i t i o n s s u c h a s m i l l i n g o r

h e a t i n g , t h e a l p h a - c r y s t a l s o f i m a t i n i b m e s y l a t e r e t a i n t h e

p o l y m o r p h i c i d e n t i t y t h u s c o n ? r m i n g t s s t a b i l i t y u n d e r t r e s s

c o n d i t i o n s .

A n o t h e r f e a t u r e o f t h e p r o d u c t made by t h e p r o c e s s o f t h e

p r e s e n t i n v e n t i o n i s i t s s t a b i l i t y t o d e g r a d a t i o n c o n d i t i o n s

s u c h a s h e a t and h u m i d i t y .

EXAMPLES

The i n v e n t i o n W i l l n o W be f u r t h e r d e s c r i b e d i n t h e f o l l o W

i n g e x a m p l e s , Which a r e i n t e n d e d t o i l l u s t r a t e t h e i n v e n t i o n .

E x a m p l e 1

1 0 0 g m s o f 4 - 4 - m e t h y l p i p e r a Z i n - 1 - y l m e t h y l ) - N - [ 4 - m e

t h y l - 3 - 4 - p y r i d i n - 3 - y l ) - p y r i m i d i n - 2 - y l a m i n o ) p h e n y l ] - b e nZamide i s added t o 1500 m l o f i s o p r o p y l a l c o h o l . To t h i s

m i x t u r e , 20 gm f Methane s u l f o n i c a c i d i s s l o W l y a d d e d a t

a m b i e n t t e m p e r a t u r e , re?uxed o r 2 h o u r s , c o o l e d t o 2 5 t o 3 0 °

C . , ? l t e r e d a n d W a s h e d W i t h i s o p r o p y l a l c o h o l , d r i e d u n d e r

reduced r e s s u r e at 45 t o 5 0 ° C . t o o b t a i n 110 g of m a t i n i b

m e s y l a t e a l p h a - f o r m .

E x a m p l e 2

1 7 k g o f - 4 - m e t h y l p i p e r a Z i n - 1 - y l m e t h y l ) - N - [ 4 - m e t h y l

3 - 4 - p y r i d i n - 3 - y l ) - p y r i m i d i n - 2 - y l a m i n o ) p h e n y l ] - b e n Z amide i s added to 255 l i t e r s o f i s o p r o p y l a l c o h o l . To t h i s

m i x t u r e , 3 . 4 kg f Methane s u l f o n i c a c i d s s l o W l y a d d e d t 2 5

t o 3 0 ° C . , m a i n t a i n e d at 7 5 t o 8 0 ° C . f o r 1 h o u r , c o o l e d t o 2 5

t o 3 0 ° C . ? l t e r e d , Washed W i t h i s o p r o p y l a l c o h o l and d r i e d

under r e d u c e d p r e s s u r e a t 4 5 t o 5 0 ° C . o b t a i n 1 9 . 5 kg o f

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7

I m a t i n i b m e s y l a t e a l p h a - f o r m . T h e p r o d u c t i s t h e n m i c r o n

i Z e d i n an i r - j e t m i l l t o o b t a i n a uniform a r t i c l e s i Z e of e s s

t h a n 2 5 m i c r o n s .

E x a m p l e 3

1 0 0 gms o f 4 - 4 - m e t h y l p i p e r a Z i n - 1 - y l m e t h y l ) - N - [ 4 - m e

t h y l - 3 - 4 - p y r i d i n - 3 - y l ) - p y r i m i d i n - 2 - y l a m i n o ) p h e n y l ] - b e nZamide s added t o 1800 m l o f n - b u t y l a l c o h o l . To t h i s mi x

t u r e , 2 0 gm o f Methane s u l f o n i c a c i d i s s l o W l y added a t

a m b i e n t t e m p e r a t u r e , h e a t e d t o 8 0 ° C . and m a i n t a i n e d f o r 2

h o u r s , c o o l e d o 2 5 t o 3 0 ° C . , ? l t e r e d a n d Washed i t h n - b u t y l

a l c o h o l , d r i e d under r e d u c e d p r e s s u r e a t 4 5 to 5 0 ° C . o b t a in

1 1 5 g o f I m a t i n i b m e s y l a t e a l p h a - f o r m .

E x a m p l e 4

F o r c e d d e g r a d a t i o n s t u d y o f i m a t i n i b m e s y l a t e a l p h a

f o r m ) .

I n i t i a l t o t a l i m p u r i t y c o n t e n t : 0 . 5 0 Wt

T o t a l i m p u r i t y c o n t e n t a f t e r 6 m o n t h s : 0 . 3 3 Wt

T o t a l i m p u r i t y c o n t e n t a f t e r 1 2 months: 0 . 4 1 Wt

The HPLC i n g l e m a x i m u m i m p u r i t y c o n t e n t o f t h e b a t c h

of m a t i n i b mesylate Was found t o vary a s f o l l o W s :

I n i t i a l s i n g l e m a x i m u m i m p u r i t y c o n t e n t : 0 . 2 3 Wt

S i n g l e m a x i m u m i m p u r i t y c o n t e n t a f t e r 6 m o n t h s : 0 . 1 1 Wt

S i n g l e m a x i m u m o t a l i m p u r i t y c o n t e n t a f t e r 1 2 m o n t h s : 0 . 1 5 Wt

Fr om t h e s e m e a s u r e m e n t s , i t c o u l d be d e t e r m i n e d t h a t t h e

i m a t i n i b m e s y l a t e a c c o r d i n g t o t h e i n v e n t i o n s s u b s t a n t i a l l y

p o l y m o r p h i c a l l y a n d c h e m i c a l l y p u r e .

TABLE

I m p u r i t y P r o ? l e o f t h e m a t e r i a l i n

s t r e s s c o n d i t i o n s

S i n g l e

BATCH STRESS Max.

NO. CONDITION DESCRIPTION i m p u r i t y P u r i t y DSC XRPD

RD/IMT-4/31 As s u c h i . e . n o P a l e y e l l o W 0.18 99.45 C o m p l i e s C o m p l i e s

s t r e s s c o n d i t i o n ) c o l o u r e d p o W d e r

6 0 ° C . f o r 4 8 h o u r s P a l e y e l l o W 0.20 99.44 C o m p l i e s C o m p l i e s

c o l o u r e d p o W d e r

1 0 5 ° C . f o r 1 2 h o u r s P a l e y e l l o W 0.17 99.49 C o m p l i e s C o m p l i e s

c o l o u r e d p o W d e r

UV 4 5 ° C . 7 5 RH P a l e y e l l o W 0.19 99.38 C o m p l i e s C o m p l i e s

f o r 1 2 h o u r s c o l o u r e d poWder

RD/IMT-4/34 As s u c h i . e . n o C r e a r n c o l o u r e d 0.33 99.26 C o m p l i e s C o m p l i e s

s t r e s s c o n d i t i o n ) p o W d e r

6 0 ° C . f o r 48 h o u r s C r e a r n c o l o u r e d 0.30 99.17 Complies C o m p l i e s

p o W d e r

1 0 5 ° C . f o r 1 2 h o u r s C r e a r n c o l o u r e d 0.32 99.18 Complies C o m p l i e s

p o W d e r

UV 4 5 ° C . 7 5 RH C r e a r n c o l o u r e d 0.34 99.18 Complies Complies

f o r 1 2 h o u r s poWder

45

Example I t W i l l b e a p p r e c i a t e d t h a t t h e i n v e n t i o n d e s c r i b e d a b o v e

T h e s t a b i l i t y o f t h e i m a t i n i b m e s y l a t e a c c o r d i n g t o t h e

invention Was s t u d i e d over a tWelve m o n t h e r i o d , t o ensure

t h a t the p r o d u c t h a d c h e m i c a l a n d p o l y m o r p h i c s t a b i l i t y . T h i s

s t u d y con?rmed h a t t h e i m a t i n i b m e s y l a t e r e t a i n e d t h e same

p o l y m o r p h i c a n d c h e m i c a l i d e n t i ty a t s i x a n d t W e l v e m o n t h s

a f t e r m a n u f a c t u r e .

The Water c o n t e n t o f t h e b a t c h o f i m a t i n i b m e s y l a t e Was

f o u nd t o vary a s f o l l o W s :

I n i t i a l Water c o n t e n t : 0.39 Wt

Water c o n t e n t a f t er 6 months: 0 . 6 1 Wt

Water c o n t e n t a f t e r 12 months: 0 . 5 8 Wt

The HPLC o t a l i m p u r i t y c o n t e n t o f t h e b a t c h o f i m a t i n i b

mesylate Was found t o vary a s f o l l o W s :

50

55

6 5

m a y b e modi?ed W i t h i n t h e s c o p e o f t h e c l a i m s .

The i n v e n t i o n c l a i m e d i s :

1 . A r o c e s s f o r t h e p r e p a r a t i o n o f h e a l p h a r y s t a l f o r m o f

t h e compound o f F o r m u l a I :

\

/N O H

W h e r e i n t h e p r o c e s s c o m p r i s e s :

8/21/2019 Us 8269003


US 8 , 2 6 9 , 0 0 3 B2

a ) s u s p e n d i n g o r d i s s o l v i n g t h e compound f t h e F o r m u l a

I i n a s o l v e n t ;

b ) a d d i n g methane s u l f o n i c a c i d t a t e m p e r a t u r e o f 5 ° C .

to 3 0 ° C . t o t h e s u s p e n s i o n o r s o l u t i on formed n s t e p a ) ;

c ) h e a t i n g t h e m i x t u r e f o r m e d i n s t e p b ) t o a t l e a s t 7 0 ° C .

f o r l t o 2 h o u r s ; and

d ) c o o l i n g t h e m i x t u r e t o a m b i e n t t e m p e r a t u r e a n d i s o l a t

i n g t h e a l p h a c r y s t a l f o r m o f h e compound o f F o r m u l a

I I W h e r e i n the a l p h a c r y s t a l f o r m o f the compound o f

Formula I i s a s t a b l e c r y s t a l form a n d W h e r e i n t h e a l p h a

c r y s t a l f o r m o f t h e compound o f F o r m u l a I I i s c h a r a c

t e r i s e d b y a n X - r a y d i f f r a c t i o n p a t t e r n h a v i n g p e a k s a t

2 - t h e t a 4 . 8 7 ° , l 0 . 4 0 ° , l 8 . 5 6 ° a n d 2 4 . 8 2 ° and a b s e n c e o f

p e a k s a t 5 . 8 7 ° , 9 . 7 2 ° a n d 2 0 0 ° .

2 . The r o c e s s a c c o r d i n g t o c l a i m 1 , W h e r e i n t h e s o l v e n t i s

a n alco ho l o r a ketone.

3 . The r o c e s s a c c o r d i n g t o c l a i m 2 , W h e r e i n t h e a l c o h o l i s

a C2 o C4 a l c o h o l .

4 . The r o c e s s a c c o r d i n g t o c l a i m 1 , W h e r e i n t h e s o l v e n t i s

s e l e c t e d f r o m i s o p r o p a n o l , n - p r o p a n o l , n - b u t a n o l , t - b u t a n o lo r m e t h y l i s o b u t y l k e t o n e .

5 . The p r o c e s s a c c o r d i n g to c l a i m 1 W h e r e i n t h e m i x t u r e

f o r m e d i n s t e p b ) i s h e a t e d t o a t l e a s t 8 0 ° C . i n s t e p c ) .

6 . The r o c e s s a c c o r d i n g t o c l a i m 1 , f u r t h e r c o m p r i s i n g e )

m i c r o n i Z i n g t h e a l p h a c r y s t a l f o r m o f h e compound o f f o r

m ula I i n an i r j e t m i l l t o o b t a i n a p a r t i c l e s i Z e o f e s s t h a n 25

m i c r o n s .

7 . The p r o c e s s a c c o r d i n g t o c l a i m 1 W h e r e i n t h e a l p h a

c r y s t a l f o r m o f t h e compound f f o r m u l a I I i s f u r t h e r c h a r a c

t e r i Z e d b y a d i f f e r e n t i a l s c a n n i n g t h e r m o g r a m a c c o r d i n g t o

F I G . 2 .

1 0

8 . A r o c e s s f o r t h e p r e p a r a t i o n o f h e a l p h a r y s t a l f o r m o f

t h e compound o f F o r m u l a I :

5 n

HN N

1 0 \

1 5/N

W h e r e i n t h e p r o c e s s c o m p r i s e s :

a ) s u s p e n d i n g o r d i s s o l v i n g t h e compound f the F o r m u l a

2 0 I i n a s o l v e n t ;

HN N

\N

\

30

b ) a d d i n g methane s u l f o n i c a c i d t a t e m p e r a t u r e o f 5 ° C .

to 3 0 ° C . to t h e s u s p e n s i o n o r s o l u t i o n formed n s t e p a ) ;

c ) h e a t i n g t h e m i x t u r e f o r m e d i n s t e p b ) t o a t l e a s t 7 0 ° C .

f o r l t o 2 h o u r s ; and

d ) c o o l i n g t h e m i x t u r e t o a m b i e n t t e m p e r a t u r e a n d i s o l a ti n g t h e a l p h a c r y s t a l f o r m o f h e compound o f F o r m u l a

I I W h e r e i n the a l p h a c r y s t a l f o r m o f t h e compound o f

Formula I I i s a s t a b l e c r y s t a l form and h a s an X-ray

d i f f r a c t i o n p a t t e r n h a v i n g p e a k s a t 2 - t h e t a 4 . 8 7 0 ° ,

l 0 . 4 0 0 ° , l l . l 5 0 ° , l l . 8 4 0 ° , l 2 . l 3 0 ° , l 4 . 8 5 0 ° , l 6 . 4 4 0 ° ,l 7 . 6 2 0 ° , l 8 . 0 4 0 ° , l 8 . 5 6 0 ° , l 9 . 0 l 0 ° , l 9 . 7 8 0 ° , 2 l . 2 0 0 ° ,2 l . 4 8 0 ° , 2 l . 6 2 0 ° , 2 2 . 4 0 0 ° , 2 2 . 5 7 0 ° , 2 3 . 0 9 0 ° , 2 3 . 6 9 0 ° ,2 4 . 8 2 0 ° , 2 6 . 2 3 0 ° , 2 7 . l 9 0 ° , 2 7 . 8 4 0 ° , 2 7 . 9 6 0 ° , 2 8 . 4 6 0 ° ,3 l . 8 7 0 ° , 3 8 . 0 0 0 ° , 3 8 . 9 5 0 ° , 3 9 . 2 0 0 ° , 3 9 . 3 9 0 ° , 3 9 . 5 5 0 ° ,4 2 . 9 5 0 ° , 4 3 . 0 5 0 ° , 4 3 . 2 9 0 ° , 4 5 . 5 4 0 ° a n d 4 5 . 9 6 0 ° .

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